When injury, disease or surgery disrupts the normal architecture of body tissues such as the skin, eye and palmar aponeurosis of the hand, the body instigates a complex cascade of events collectively known as wound healing. These processes in the early human foetus lead to total regeneration of the damaged or destroyed tissue. However, in post natal humans, although the capacity of the outer layer of the skin, the epidermis, for regeneration is phenomenal, wound healing of the deeper skin layer, the dermis, is often accompanied by a fibroproliferative response that leads to the formation of a fibrotic scar. The tissues of the eye, particularly the cornea, often scar after surgery or trauma which reduces the vision of the individual. Dupuytren's disease affects the palmar aponeurosis of the hand. This condition is caused by scarring and fibrosis that causes contraction of the palmar structure, thus pulling the fingers permanently down towards the palm.
The severity of scarring of an individual in response to injury, disease or surgery is highly variable and depends on multiple factors, such as infection, wound extent and orientation. Nevertheless, even when all these factors are taken into account, the severity of so-called “normal” scarring still varies dramatically between individuals. This variation in the severity of scarring of the skin is perhaps most dramatically illustrated by the comparison of normal scars with pathological scarring conditions such as hypertrophic or keloid scarring.
Hypertrophic scars are characterised by extensive scar tissue, which contains an excess of collagen and is highly cellular (Rockwell et al., 1989. Plast. Recon. Surg. 84: 827-837, the disclosure of which is incorporated herein by reference). Redness, hypopigmentation or hyper-pigmentation of the affected area often accompanies these scars. Patients can also suffer from hyperaesthesia and pruritus and, in addition, contraction of scars located over a joint can lead to a loss of mobility. This distressing pathological condition can affect substantial numbers of patients who have suffered various types of skin trauma, with children under the age of four years particularly prone. Two of the latest estimates of the proportion of paediatric burns patients who suffer from this condition are as high as 44 and 60%.
At present there is no method of predicting which individuals will develop these scars, nor any method of preventing their formation or that of normal scars, nor any treatment. Effective therapies for both pathological scarring and normal scarring accordingly continue to be sought.
It has been suggested for some time that insulin and its related growth factor family, insulin-like Growth Factors (hereinafter referred to as IGFs), may improve the rate of re-epithelialisation of wounds. U.S. Pat. Nos. 5,591,709 and 5,461,030 of Life Medical Sciences Inc (the disclosures of which are incorporated herein by reference) describe topically applied wound treatment formulations which are useful for treating wounds by accelerating wound healing. The formulations may, for example, contain insulin or IGF, together with further specified components. The formulations were tested on guinea-pigs for speed of wound healing, and it was observed in passing (see e.g. U.S. Pat. No. 5,591,709, column 23, line 46, to column 24, line 3) that a certain agarose gel based formulation produced a relatively soft, smooth, aesthetic and natural-looking scar in guinea-pig skin. However, no corresponding effect on the healing of human skin was reported, and the disclosure is unclear as to which specific hormone or hormone mixture was present in the agarose formulation for which the improved guinea-pig scar was noted. Although many groups (such as Pierre et al., 1998. J. Trauma. 44:34-345, the disclosure of which is incorporated herein by reference), have shown that systemic treatment with insulin and IGFs increases the speed of wound closure, the effect of these agents on human scar tissue formation has never before been investigated.
Peroxisome proliferator-activated receptors (PPARs) are known to control many cellular and metabolic processes and exist as three isotypes in vertebrates, PPARα, PPARβ/δ and PPARγ (Hanley et at, 1998 Journal of Investigative Dermatology, Vol. 110, pp. 368-375; Michalik et al., 2001, Journal of Cell Biology, Vol. 154, pp. 799-814). Each isoform displays differential tissue distribution in vertebrates, suggesting a specific role for each isoform. Both PPARα and PPARγ have been shown to play important roles in lipid homeostasis and inflammation. PPARα is important in skin development and wound healing, with PPARα ligands being able to accelerate fetal rat epidermal development. Although levels of PPARs reduce after birth, wounding or hair plucking may stimulate expression of these ligands. PPARγ agonists may mimic the effect of insulin. However, PPAR agonists have not hitherto been shown to have any anti-scarring activity when applied to human skin.
To date, with regard to the development of anti-scarring therapies, attention has been focused on the finding that transforming growth factor beta 1 (TGFβ1) enhances scarring. Many groups have worked to develop ways of inhibiting TGFβ1, with some success. Methods used have included TGFβ1 receptor blocking antibodies or the application of mannose-6-phosphate, which prevents the activation of latent TGFβ1. The main problem with these approaches is that induction of scarring is not the only function of TGFβ1. TGFβ1 is known for its angiogenic properties. In addition, application of low doses of TGFβ1 is known to enhance re-epithelialisation of wounds. Thus, although the blocking of either the action or activation of TGFβ1 in incisional wounds may result in the reduction of scarring with relatively few deleterious side effects, the healing of larger wounds, which rely on epithelial migration for closure, may be delayed.
The initial induction of myofibroblasts, the concentration of which rises to a peak in the first few days of wound healing (the “pre-peak” phase) is thought to be due to the large amounts of growth factors such as TGFβ1 released early in the repair process. TGFβ1 is released in large quantities from the degranulating platelets within the forming clot, it is also secreted by multiple types of immune cells which migrate into the wound area and all of the major cell types participating in the repair process. TGFβ is linked with fibrosis in many different body tissues and is known to be a strong inducer of differentiation of fibroblasts into myofibroblasts in vitro. Thus, TGFβ is the most probable cause of the induction of the myofibroblast phenotype that occurs during wound repair.